Inducible Ventricular Tachyarrhythmias Research Articles

Sex-specific differences in mortality and neurocardiac interactions in the Kv1.1 knockout mouse model of sudden unexpected death in epilepsy (SUDEP).

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy with possible sex-specific risk factors, although the exact relationship between sex and SUDEP remains unclear. To investigate this, we studiedKcna1knockout (Kcna1-/-) mice, which lack voltage-gated Kv1.1 channel subunits and are widely used as a SUDEP model that mirrors key features in humans.To assess sex differences, we first performedsurvival analysis, EEG-ECG recordings, seizure threshold testing and retrospective analysis of previous intracardiac pacing data. We then applied a novel modelling approach across organs (organomics) to uncover potential sex-specific differences in brain-heart communication. Our findings revealed femaleKcna1-/-mice have significantly longer lifespans than males, suggesting lower SUDEP rates. Although no sex differences were found in seizure frequency, duration, burden, susceptibility or interictal heart rate variability, females showed a higher incidence of bradycardia during spontaneous seizuresthan males, as well asresistance to inducible ventricular tachyarrhythmias in response to programmed electrical stimulation.Two captured SUDEP events, one per sex,displayed similar patterns of ictal bradycardiain both sexes,progressing to postictal cardiorespiratory failure. Going beyond traditional seizure and cardiac metrics, organomics analysis revealed that seizures affect brain-heart communication differently between sexes. Females exhibited more effective resetting of brain-heart interactions postictally than males.This finding may contribute to the lower SUDEP risk in females and underscores the complex interplay between sex, cardiac function and brain-heart communication in determining SUDEP susceptibility. Furthermore, seizure-resetting measures could represent a promising class of biomarkers for SUDEP risk stratification. KEY POINTS: Female Kcna1-/- mice live longer than males, suggesting lower sudden unexpected death in epilepsy (SUDEP) rates. There are no sex differences in seizure metrics or interictal heart rate variability. Females show more bradycardia during seizures and are resistant to inducible ventricular tachyarrhythmias. Seizures affect brain-heart communication differently between the sexes. Seizures in females reset brain-heart interactions more effectively postictally, potentially lowering SUDEP risk.

Prognostic parameters predict cardiac events in Brugada syndrome: a meta-analysis

Abstract Background Brugada syndrome (BrS) is recognized as a cause of sudden cardiac death (SCD), ventricular tachycardia or ventricular fibrillation (VT/VF). However, the prognosis varies among the patients with Brugada electrocardiograph (ECG) pattern. Furthermore, there is no prognostic tool to predict the worsening cardiac outcomes in BrS. Objectives Primary outcome was to assess the association between risks including patient history, ECG pattern, electrophysiology study (EPS) findings and cardiac events which is identified as VT/VF or SCD. Method We performed a meta-analysis of prospective and retrospective cohort studies which assessed the risks and cardiac events in patients with BrS. Pooled hazard ratios (HRs) was analyzed by using Random-effect model. Result A total of 27 studies involving 15,990 BrS patients. Of these, 17 were retrospective studies and 10 were prospective studies. In univariate analysis, the risks including male, aborted SCD, QRS duration≥120 msec, fragmented QRS (multiple spikes within the QRS complex in lead V1-V3), late potential (positive terminal filtered QRS complex of signal-averaged ECG), sinus node dysfunction or inducibility of ventricular tachyarrhythmias during EPS associated with a higher risk of cardiac events in BrS. In multivariate analysis, higher risks of cardiac events were associated in BrS patients with history of syncope (HR 2.65, 95% confidence interval (CI): 1.68-4.19, I2 = 54 %, p-value <0.001), family history of SCD (HR 2.64, 95%CI:1.39-5.01, I2 = 0%, p-value = 0.003), prior VF (HR 14.52, 95%CI: 3.36-62.84, I2 = 62%, p-value <0.001), type 1 Brugada ECG pattern (HR 2.07, 95%CI: 1.13-3.79, I2 = 0%, p-value = 0.018), spontaneous type 1 ECG pattern (HR 1.91, 95%CI: 1.01-3.61, I2 = 58%, p-value = 0.046), early repolarization pattern (HR 2.78, 95%CI: 1.9-4.07, I2 = 0%, p-value < 0.001) and history of atrial fibrillation before BrS diagnosis (HR 1.82, 95%CI: 1.03-3.23, I2 = 49%, p-value = 0.039) (Table 1). Conclusion Our findings suggest that patient history, ECG pattern, EPS findings can predict the cardiac events. Introducing a risk prediction model could aid in early management of BrS.

Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.

Activation of PKC affects the ventricular restitution properties and arrhythmogenesis through L-type Ca+ current.

To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs). Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli-extra-stimulus (S1-S2) method and dynamic S1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol-12-myristate-13-acetate (PMA) (100nM) (n=15) greatly steepened the restitution curves (Smax>1) (p<.01) at each site compared to the control group (n=15). Furthermore, treatment with PMA also induced larger spatial dispersions of Smax (p<.05) and decreased the thresholds of the VA and APD alternans (p<.01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500nM) (n=10), reversibly flattened the APD restitution curves at each site (Smax<1), decreased the spatial dispersions of Smax, and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca2+ current was significantly increased by addition of PMA compared with control (CTL) group (p<.05). Antagonize this current with verapamil (n=10) can fully inhibited the PMA induced increasing of Smax and inducibility of VA and alternans. PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca2+ influx.

Impact of phase-correction of late-gadolinium enhancement images on quantification of scar metrics and in-silico VT-modelling in patients with an ischemic cardiomyopathy

Abstract Background Late gadolinium enhancement (LGE) is used to perform tissue characterization and has become the cornerstone to guide treatment of ventricular tachyarrhythmia (VT). Traditionally, LGE acquisition is reconstructed in two distinct forms: non-phase corrected magnitude (MIR) and phase-corrected inversion recovery (PSIR) images. However, the influence of MIR vs. PSIR on the quantification of scar metrics and the repercussion on estimating myocardial arrhythmogenicity have not been comprehensively explored. Aim This study investigated the influence of PSIR and MIR LGE on the quantification of scar metrics in a randomly selected cohort of patients with ischemic cardiomyopathy who had undergone imaging prior to ICD implantation and had received device therapy during follow-up. In addition, this study assessed how these image variations affect functional estimation of arrhythmogenicity using computational modelling. Methods ADAS 3D LV was used to generate scar maps from 2D PSIR and MIR LGE images in 10 patients. The extent of variation in scar-characteristics was evaluated by quantifying the borderzone (BZ), scar core, and conduction corridors. Electrical simulations were performed on the patient-specific anatomical models using the Virtual Induction and Treatment of Arrhythmias (VITA) framework. VITA was used to assess the electrical vulnerability of potential reentrant channels and provided the number of inducible VTs and their corresponding round-trip-time (RTT), an equivalent of VT cycle-length. Results Scar quantification using PSIR LGE resulted in a significantly larger BZ (22.1±23.7g vs. 6.2±2.7g, p &amp;lt;.001) and scar core (43.5±21.5g vs. 10.5±4g, p =.047). Furthermore, both the absolute number (6.8±4 vs. 3.4±1.5, p = .031) and weight (13±13.1g vs. 1.4±0.8g, p =.018) of conduction corridors were also higher using PSIR. VTs were inducible in 8 PSIR-models and 7 MIR-models. Despite large differences in scar characteristics, VITA metrics were not significantly different between PSIR and MIR derived models. Although, the absolute number of inducible VTs were larger for PSIR (6.2±5.4 vs. 3.4±3.1), non-parametric testing using Wilcoxon signed-rank test did not demonstrate a significant difference (Z = -1.334, p =.139). A comparable, non-significant difference was observed for mean- (117±78 vs. 79±60, p =.257) and max-RTT (181±141 vs. 120±103, p =.294) between PSIR and MIR derived models. Conclusion PSIR resulted in significantly larger BZ, scar core area, and conduction corridors. While the absolute, VITA-derived estimation of myocardial arrhythmogenicity, including inducible VTs and RTT, were higher in the PSIR-based quantification, these differences did not reach statistical significance. These results highlight important differences between two clinically applied image reconstruction techniques for the assessment of arrhythmogenic substrate, emphasizing the need for additional investigation and refinement of scar quantification techniques.

Histological and functional assessment of a Takotsubo cardiomyopathy model established by immobilization stress.

Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, resembles acute heart failure syndrome but lacks disease-specific diagnosis and treatment strategies. TTC accounts for approximately 5-6% of all suspected cases of acute coronary syndrome in women. At present, animal models of TTC are often created by large amounts of exogenous catecholamines such as isoproterenol. However, isoproterenol injection cannot fully simulate the onset of stress-induced cardiomyopathy in humans since stress is not an instantaneous event. Rats were immobilized for 6h per day for 1-14 days. To examine whether the TTC model was successful, echocardiography was employed; Elisa detected serum sympathetic activation markers; and the Open-Field test (OFT) was used to analyze behavioral changes in rats after stress. Western blot and histology were used to assess sympathetic remodeling, inflammation levels, and fibrosis; qRT-PCR was used to explore the levels of fibrosis and myocardial hypertrophy. The electrical stability of ventricular was determined by electrophysiological testing. The rats showed severe stress behavior and local sympathetic remodeling of the heart after only 1 day of stress. After 3 days of stress, the induction of ventricular tachyarrhythmia increased prominently. The highest incidence of TTC in rats was at 5 days of immobilization stress. The pathological left ventricular remodeling caused by immobilization (IMO) stress includes inflammatory infiltration, fibrosis, and myocardial hypertrophy. Our study confirms the hypothesis that IMO stress can mimic Takotsubo cardiomyopathy, and the various effects on the heart depending on the duration of IMO stress. We observed the highest incidence of TTC occurred after 5 days of stress. Furthermore, there is a gradual occurrence of electrical and structural remodeling as the stress duration prolongs.

Alcohol and caffeine synergistically induce spontaneous ventricular tachyarrhythmias: ameliorated with dantrolene treatment.

Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase cardiac arrhythmia risk. However, it is unknown whether alcohol and caffeine co-consumption can synergistically enhance cardiac arrhythmogenesis. The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis. A binge drinking rat model (alcohol 2 g/kg, intraperitoneal, every other day for 3 times) was used. Rats (4 months old, both sexes) were randomized into the following 4 groups: binge alcohol-only group (A) (n = 8), nonalcohol, caffeine-only (60 mg/kg, intraperitoneal) group (C) (n = 8), binge alcohol plus caffeine group (A+C) (n = 8), and binge alcohol + caffeine + dantrolene group (A+D) (n = 7, treated with dantrolene 10 mg/kg before each alcohol injection). We also investigated whether alcohol induces Ca2+ sparks and dantrolene treatment attenuates alcohol-induced Ca2+ leak in ventricular myocytes. No arrhythmia was induced with caffeine alone (group C, n = 0 of 8) or alcohol alone (group A, n = 0 of 8). However, alcohol + caffeine induced spontaneous ventricular tachyarrhythmias in all rats (group A+C, n = 8 of 8; P < .001 vs group C or A). Dantrolene prevented ventricular tachyarrhythmia induction in all 7 rats (group A+D, n = 0 of 7; P < .001 vs group A+C). In isolated ventricular myocytes, alcohol significantly increased Ca2+ sparks and dantrolene treatment reduced alcohol-induced Ca2+ sparks. Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca2+ sparks invitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias invivo.

In-hospital predictors for primary prevention of sudden death after acute myocardial infarction with cardiac dysfunction

BackgroundCurrent guidelines recommend prophylactic defibrillator implantation in patients with acute myocardial infarction (AMI) and left ventricular ejection fraction (LVEF) ≤40 % or LVEF ≤35 % plus heart failure symptoms or inducible ventricular tachyarrhythmias during an electrophysiology study at 40 days after AMI or 90 days after revascularization. In-hospital predictors of sudden cardiac death (SCD) after AMI during the index hospitalization remain unsettled. We sought to examine in-hospital predictors of SCD in patients with AMI and LVEF ≤40 % evaluated during the index hospitalization. MethodsWe retrospectively evaluated 441 consecutive patients with AMI and LVEF ≤40 % admitted to our hospital between 2001 and 2014 (77 % male gender; median age: 70 years; median hospitalization length: 23 days). The primary endpoint was a composite of SCD or aborted SCD at ≥30 days after AMI onset (composite arrhythmic event). LVEF and QRS duration (QRSd) on electrocardiography were measured at a median of 12 days and 18 days, respectively. ResultsDuring a median follow-up of 7.6 years, the incidence of composite arrhythmic events was 7.3 % (32 of 441 patients). In multivariable analysis, QRSd ≥100 msec (beta-coefficient = 1.54, p = 0.003), LVEF ≤23 % (beta-coefficient = 1.14, p = 0.007), and onset-reperfusion time > 5.5 h (beta-coefficient = 1.16, p = 0.035) were independent predictors of composite arrhythmic events. The combination of these 3 factors was associated with the highest rate of composite arrhythmic events compared with 0–2 factors (p < 0.001). ConclusionsThe combination of QRSd ≥100 msec, LVEF ≤23 %, and onset-reperfusion time > 5.5 h during the index hospitalization provides precise risk stratification for SCD in patients early after AMI.

Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts.

The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation. Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI). In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n=17), and a basket catheter was positioned in the left ventricle (n=6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS. During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from-18.3% ± 6.3% to-2.1% ± 14.7%) and ARI dispersion (from 104ms2 [1 to 1,108ms2] to -108ms2 [IQR: -588 to 30ms2]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P< 0.05). After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.

Arrhythmic CArdiac DEath in MYotonic dystrophy type 1 patients (ACADEMY 1) study: the predictive role of programmed ventricular stimulation

Myotonic dystrophy type 1 (DM1) predisposes to the development of life-threatening arrhythmias and sudden cardiac death. Our study aimed to evaluate the prognostic value of programmed ventricular stimulation (PVS) in DM1 patients with conduction system disease. Arrhythmic CArdiac DEath in MYotonic dystrophy type 1 patients (ACADEMY 1) is a double-arm non-randomized interventional prospective study. Myotonic dystrophy type 1 patients with permanent cardiac pacing indication were eligible for the inclusion. The study population underwent to pacemaker (PM) or implantable cardioverter-defibrillator (ICD) implantation according to the inducibility of ventricular tachyarrhythmias at PVS. Primary endpoint of the study was a composite of appropriate ICD therapy and cardiac arrhythmic death. The secondary study endpoint was all-cause mortality. Seventy-two adult-onset DM1 patients (51 ± 12 years; 39 male) were enrolled in the study. A ventricular tachyarrhythmia was induced in 25 patients (34.7%) at PVS (PVS+) who underwent dual chambers ICD implantation. The remaining 47 patients (65.3%) without inducible ventricular tachyarrhythmia (PVS-) were treated with dual-chamber PM. During an average observation period of 44.7 ± 10.2 months, nine patients (12.5%) met the primary endpoint, four in the ICD group (16%) and five (10.6%) in the PM group. Thirteen patients died (18.5%), 2 in the ICD group (8%) and 11 in PM group (23.4%). The Kaplan-Meier analysis did not show a significantly different risk of both primary and secondary endpoint event rates between the two groups. The inducibility of ventricular tachyarrhythmias has shown a limited value in the arrhythmic risk stratification among DM1 patients.

Abstract 10597: Epidural Sympathetic Afferent Blockade by Resiniferatoxin Reverses Vagal Dysfunction Following Myocardial Infarction

Introduction: Myocardial infarction (MI) induces sympathovagal imbalance, predisposing for ventricular tachyarrhythmias (VT). Thoracic epidural anesthesia reduces VT burden through sympathetic blockade. However, it is unknown if sympathetic afferent activation may cause vagal dysfunction, and if blockade of these spinal afferents can improve vagal function and reduce VT burden. Methods: Chronic MI was percutaneously created in Yorkshire pigs (n=8). In terminal experiments 6 to 8 weeks post MI, an epidural catheter was placed at the C7-T1 epidural space. After sternotomy, a 56 electrode sock was placed over the ventricles to record activation recovery intervals (ARI, surrogate of action potential duration). Effective refractory periods (ERP) were assessed via extra-stimulus pacing and left ventricular (LV) pressure monitored via a pressure catheter. Vagal function was assessed by baroreflex sensitivity (BRS) after phenylephrine (3 μg/kg, IV). ARIs, ERP, LV function, and BRS were checked before and after epidural RTX (0.6 μg/kg/ml). VT inducibility was assessed by endocardial extra-stimulus pacing from the right ventricular apex. Results: Epidural RTX led to a modest hemodynamic response peaking at 10.2 ± 4.2 min post-RTX with stabilization by 118 ± 15 min, characterized by increased LV systolic pressure (121±5.6 to 133±9.7 mmHg; p =ns) and contractility (1411±74 to 1514±163 mmHg/s; p =ns). While ARI and atrial/ventricular ERP did not change significantly, BRS was significantly augmented by 2 hrs (2.1±0.6 to 4.3±0.8 ms/mmHg, p &lt;0.01). 9/9 animals in our chronic MI model were inducible for VT by extra-stimulus pacing whereas only 1/6 were inducible for VT after epidural RTX ( p &lt;0.001). Conclusion: Blockade of nociceptive spinal sympathetic afferents by RTX augments reflexive vagal function without altering basal cardiac function. Blockade of nociceptive afferents and restoration of parasympathetic function alone may be sufficient to suppress VT.

Electrophysiological Study Prognostic Value and Long-Term Outcome in Drug-InducedType1Brugada Syndrome: The IBRYD Study.

This study aimed to retrospectively assess long-term outcome and the prognostic role of electrophysiological study (EPS) for risk stratification of drug-induced type 1 Brugada syndrome (BrS) patients. BrS is a hereditary cardiac disease, predisposing to sudden cardiac death. Few real-world data are available on long-term outcomes of drug-induced type 1 BrS patients, and questions about risk stratification still remain unanswered. The IBRYD (Italian Brugada Syndrome) study is a multicenter observational retrospective study. A total of 226 drug-induced type 1 BrS patients were enrolled from 9 Italian tertiary referral institutions. Primary endpoint was a composite of appropriate implantable cardioverter-defibrillator (ICD) therapy and sudden cardiac death. The authors further assessed clinical predictors to ICD implantation, as well as for arrhythmia induction at EPS, along with EPS as potential risk factor for the outcomes of interest. 142 patients (62.8%) received an ICD due to syncope and/or inducible ventricular tachyarrhythmias at EPS. During a median follow-up of 106months, 11 patients (4.9%) experienced primary outcome events. The ICD therapy median annual incidence over 8 years was 0.38% (interquartile range: 0% to 1.47%). Ventricular tachyarrhythmia inducibility during EPS was not predictive of arrhythmic events in ICD recipients versus non-ICD patients and in symptomatic versus asymptomatic subgroups, showing a low positive predictive value (9.6% and 8.9%, respectively) versus a high negative predictive value (96.6% and 95%, respectively). The authors reported 29 ICD-related complications and 4.9% inappropriate shocks. Drug-induced type 1 BrS patients have a very low arrhythmic risk. Clinical decision for implantation is supported by syncope and/or EPS positivity, though they fail to stratify high-risk patients. A better risk-to-benefit ratio should be pursued, considering both arrhythmic risk and ICD-related complications.

Risk stratification in asymptomatic patients with Brugada syndrome: Utility of multiple risk factor combination rather than programmed electrical stimulation.

The prognostic value of programmed electrical stimulation (PES) in Brugada syndrome (BrS) remains controversial. Asymptomatic BrS patients generally have a better prognosis than those with symptoms. The purpose of this study was to evaluate the value of nonaggressive PES with up to two extra stimuli and predict clinical factors for risk stratification in asymptomatic BrS patients. The study enrolled 193 consecutive asymptomatic BrS patients with type 1 ECG (mean age: 50 ± 13 years, 180 males) who underwent PES using a nonaggressive uniform protocol. Cardiac events (CEs: sudden cardiac death or ventricular tachyarrhythmia) during the follow-up period were examined. During a mean follow-up of 101 ± 48 months, seven asymptomatic patients (3.6%) had a CE. The incidence of CEs was not different between patients with and without inducible ventricular tachyarrhythmia by PES (p = .51). The clinical significance of risk factor combinations, including spontaneous type 1 ECG, family history of sudden cardiac death, QRS duration in lead V2 , and presence of J wave, was evaluated. Using the Kaplan-Meier method according to the number of risk factors, the prevalence of CE in patients with three or four risk factors was determined to be significantly higher than in those with one risk factor (p = .02 and p = .004, respectively). The present study suggests that inducibility of ventricular tachyarrhythmia does not predict future CEs in asymptomatic BrS patients. Combination analysis of the other four clinical risk parameters may be effective for risk assessment.

Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia\u2013reperfusion injury

Studies have demonstrated that diabetic (db/db) mice have increased susceptibility to myocardial ischemia–reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control (db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Cai transient duration, Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr17-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.

Long-term prognosis in patients with non-type 1 Brugada ECG: results from a large Japanese cohort of Brugada syndrome

Abstract Background Most recent consensus conference report recommends Brugada syndrome (BrS) is diagnosed in patients with ST segment elevation with spontaneous, drug-induced or fever-induced type 1 morphology. Prognosis in patients with type 2 or 3 ECG without drug-induced or fever-induced type 1 ECG is still unknown. Purpose To evaluate a long-term prognosis in patients with non-type 1 Brugada ECG in a large Japanese cohort of BrS (The Japan Idiopathic Ventricular Fibrillation Study [J-IVFS]). Methods From 528 patients in J-IVFS, a total of 28 consecutive non-type 1 patients (54±14 years, all male, previous sustained ventricular tachyarrhythmias (VTs) 1, syncope 11, asymptomatic 16) were enrolled. Cardiac events (CI: sudden cardiac death or VTs) during the follow-up period were evaluated, and risk factors for the cardiac events were assessed. Results During a mean follow-up period of 111±91 months (median 134 months), 4 patients experienced cardiac events (1.5%/yr), who all had received implantable cardioverter defibrillator implantation. There was no statistically significant clinical risk factor for cardiac events. However, the incidences of cardiac events tended to be higher in symptomatic patients (CI: 25.0, non-CI: 6.3%, p=0.17), those with wide QRS duration &amp;gt;90 msec in lead V2 (CI: 30.0, non-CI: 6.3%, p=0.11), and those with inducible VTs (CI: 21.1, non-CI: 0%, p=0.20), as determined by the Kaplan-Meier method. The annual incidences of cardiac events in patients with symptom, wide QRS duration &amp;gt;90msec in lead V2, or inducible VTs were 2.8, 3.5, and 2.0%/yr, respectively. The incidences of cardiac events were significantly higher in patients with all these 3 factors (9.9%/yr) than those without (p=0.01). Conclusions Our large-scaled multicentre study revealed long-term prognosis in patients with non-type 1 Brugada ECG. The combination of symptom, wide QRS duration in lead V2, and inducible VTs may be useful to evaluate risk for cardiac events. The patients with all these parameters showed high risk for cardiac events and need to be carefully followed. Funding Acknowledgement Type of funding source: None

Impact of outflow tract obstruction in the management of atrial fibrillation in hypertrophic cardiomyopathy: insights from the national readmission database

Abstract Background Atrial fibrillation (AF) is commonly encountered in patients with Hypertrophic Cardiomyopathy (HCM). Presence of AF in this high risk population is detrimental due to its effect on hemodynamics, diastolic function and potential induction of ventricular tachyarrhythmias. For these reasons a rhythm control strategy is highly desirable, and yet catheter ablation of AF is consistently inefficacious with poorer overall outcomes. We hypothesize that in HCM presence of outflow tract obstruction by virtue of its effect on left atrial hemodynamics, altered circulatory flow patterns in the pulmonary veins, and stretch related triggered activities would create an arrhythmogenic substrate, and have significant impact on the outcomes of catheter ablation of AF. In this study, we aimed to evaluate AF ablation outcomes based on the presence or absence of outflow tract obstructions in patients with HCM. Methods We conducted a retrospective study using the AHRQ-HCUP National Readmission Database for the years 2016–17. All adults (≥18 years) with HCM undergoing AF ablation procedures were identified using ICD-9 codes. The cohort was divided into two groups; Obstructive HCM (Group A) and Non-Obstructive HCM (Group B) Multivariate regression analysis was utilized to adjust for confounders. Independent risk factors for in-hospital mortality were identified using a proportional hazards model. Complications were defined as per the Agency for Health Care Research and Quality guideline. Results From a total of 71,451,419 patients in the NRD registry, 97 patients with HCM were identified and formed the study cohort. When divided based on the presence or absence of outflow tract obstruction, there were 25 patients with Obstructive HCM and 72 patients with Non-obstructive HCM. Both groups were similar in clinical characteristics including CHADVASc scores and Charlson Comobidity indices as outlined in Table 1. Procedural outcome analysis revealed higher 30-day cardiac readmissions in the Obstructive HCM group compared to Non-obstructive HCM (25.2% vs 7.97%, p=0.049). The Obstructive HCM group had higher rates of atrial arrhythmias, 57.97%, compared to 32.44% in the non-obstructive HCM group, and heart failure exacerbations, 41.27% vs 25.82%. However, both indices did not reach statistical significance. The procedural complications rates tended to be higher in the non-obstructive HCM group, 10.8% vs. 5.6% in the Obstructive HCM group (p=0.54). Conclusions Presence of an obstructive component to HCM is associated with significantly increased short term cardiac readmissions predominantly driven by recurrent atrial arrhythmias and heart failure. These findings suggest negative influence of altered cardiac hemodynamics related to outflow tract obstruction on atrial arrhythmias. The arrhythmogenic substrate of HCM may therefore be different and less amenable to catheter ablation. HCM ablation outcomes Funding Acknowledgement Type of funding source: None

Reverse electromechanical modelling of diastolic dysfunction in spontaneous hypertensive rat after sacubitril/valsartan therapy.

AimsHypertension is a significant risk for the development of left ventricular hypertrophy, diastolic dysfunction, followed by heart failure and sudden cardiac death. While therapy with sacubitril/valsartan (SV) reduces the risk of sudden cardiac death in patients with heart failure and systolic dysfunction, the effect on those with diastolic dysfunction remains unclear. We hypothesized that, in the animal model of hypertensive heart disease, treatment with SV reduces the susceptibility to ventricular arrhythmia.Methods and resultsYoung adult female spontaneous hypertensive rats (SHRs) were randomly separated into three groups, which were SHRs, SHRs treated with valsartan, and SHRs treated with SV. In addition, the age‐matched and weight‐matched Wistar Kyoto rats were considered as controls, and there were 12 rats in each group. In vivo ventricular tachyarrhythmia induction and in vitro optical mapping were used to measure the inducibility of ventricular arrhythmias and to characterize the dynamic properties of electrical propagation. The level of small‐conductance Ca2+‐activated potassium channel type 2 (KCNN2) was analysed in cardiac tissue. Compared with SHR with left ventricular hypertrophy, treatment with SV significantly improved cardiac geometry (relative wall thickness, 0.68 ± 0.11 vs. 0.76 ± 0.13, P < 0.05) and diastolic dysfunction (isovolumetric relaxation time, 59.4 ± 3.2 vs. 70.5 ± 4.2 ms, P < 0.05; deceleration time of mitral E wave, 46 ± 4.8 vs. 42 ± 3.8, P < 0.05). The incidence of induced ventricular arrhythmia was significantly reduced in SHR treated with SV compared with SHR (ventricular tachycardia, 1.14 ± 0.32 vs. 2.91 ± 0.5 episodes per 10 stimuli, P < 0.001; ventricular fibrillation, 1.72 ± 0.31 vs. 5.81 ± 0.42 episodes per 10 stimuli, P < 0.001). The prolonged action potential duration (APD) and increase of the maximum slope of APD restitution were observed in SHR, while the treatment of SV improved the arrhythmogeneity (APD, 37.12 ± 6.18 vs. 92.41 ± 10.71 ms at 250 ms pacing cycle length, P < 0.001; max slope 0.29 ± 0.01 vs. 1.48 ± 0.04, P < 0.001). These effects were strongly associated with down‐regulation of KCNN2 (0.38 ± 0.07 vs. 0.74 ± 0.12 ng/ml, P < 0.001). The treatment of SV also decreased the level of N‐terminal pro‐B‐type natriuretic peptide, cardiac bridging integrator‐1, and intramyocardial fibrosis of SHR.ConclusionsIn conclusion, synergistic blockade of the neprilysin and the renin–angiotensin system by SV in SHRs results in KCNN2‐associated electrical remodelling in ventricle, which stabilizes electrical dynamics and attenuates arrhythmogenesis.

Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model

BackgroundCoronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model. Methods and ResultsChronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression. ConclusionsIn a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility.

P5029Inducibility of ventricular tachyarrhythmias by up to two extrastimuli does not predict future cardiac events in asymptomatic Brugada patients: results from long-term follow-up

Abstract Background Most recent consensus conference report recommends Implantable Cardioverter Defibrillator (ICD) implantation for asymptomatic Brugada patients with spontaneous or fever-induced type-1 ECG (A-BrS) and inducible ventricular tachyarrhythmias (VTs) by up to two extrastimuli as class IIb indication. However, the validity of the inducible VTs by up to two extrastimuli in A-BrS is still unknown. Purpose To evaluate the validity of the inducibility by up to two extrastimuli in A-BrS in a large Japanese cohort of BrS (The Japan Idiopathic Ventricular Fibrillation Study [J-IVFS]). Methods A total of 193 consecutive A-BrS patients performed programmed electrical stimulation (PES) with non-aggressive uniform protocol (mean age 50±13 years, 180 males) were enrolled. PES protocol was using 2 basic pacing cycles and the order of introduction of up to 2 ventricular extra-stimuli from right ventricular apex [RVA] first, then right ventricular outflow tract [RVOT], 3 ventricular extra-stimuli from RVA then RVOT down to the minimum of 200ms. Clinical outcomes during the follow-up period were compared between A-BrS patients with and without inducible VTs by up to two extrastimuli. Results Thirty-five A-BrS (18%) had inducible VTs by up to two extrastimuli. During a mean follow-up period of 101±48 months, 7 A-BrS experienced cardiac events (sudden cardiac death [SCD] or VTs, 0.4%/yr). None of the 7 A-BrS had inducible VTs by up to two extrastimuli. The incidences of cardiac events tended to be higher in A-BrS without inducible VTs by up to two extrastimuli than in those with inducible VTs (p=0.10), as determined by the Kaplan-Meier method. In the A-BrS, the annual incidences of cardiac events in A-BrS with family history of SCD, inferolateral J wave, wide QRS duration &gt;90msec in lead V2, or inducible VT/VF by 3 extrastimuli were 0.7, 0.7, 0.6, and 0.3%/yr, respectively. Conclusions Our large-scaled multicentre study with long-term follow-up revealed the inducibility of ventricular tachyarrhythmias by up to two extrastimuli does not predict future cardiac events in A-BrS, even using non-aggressive uniform protocol. Rather, other parameters such as family history of SCD or inferolateral J wave might be helpful for risk assessment in A-BrS.

Is programmed electrical stimulation mandatory for recognition of ventricular arrhythmogenicity in heart failure?

Ischemic cardiomyopathy often presents with advanced heart failure necessitating an intensive multidisciplinary approach to management. These patients constitute a very difficult population presenting with angina and ventricular tachyarrhythmias sometimes presenting as sudden cardiac death. In those patients presenting with spontaneous ventricular tachyarrhythmias, treatment with automated intracardiac defibrillator implantation has a significant mortality benefit. In patients with significant left ventricular (LV) dilatation and a left ventricular ejection fraction ≤ 30%, guidelines state that device implantation should be preceded by programmed electrical stimulation, which demonstrates inducible ventricular tachyarrhythmia. The treatment options for patients with moderate LV dilatation and ejection fraction ≥ 30% is individualized. Devices have their associated problems. Radiofrequency ablation has mixed results. Surgical cryoablation when performed concomitantly with surgical ventricular restoration has shown promising results. But, this option remains isolated to patients eligible for surgical ventricular restoration. Programmed electrical stimulation for inducibility of ventricular tachyarrhythmias in these patients also has a questionable role. The need for programmed electrical stimulation prior to cryoablation also seems highly individualized. In this review, we discuss the mechanisms of ischemic ventricular tachyarrhythmias and treatment options in heart failure. The mechanisms of ventricular arrhythmogenesis in ischemic cardiomyopathy help in formulating novel technical modifications for cryoablation when performed concomitantly with surgical ventricular restoration.